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By the end of this lecture you should be able to:
• Define ‘pharmacokinetics’ and ‘pharmacodynamics’
• Define ‘elimination’, ‘metabolism’ and ‘excretion’ • Describe the main pathways of drug metabolism
and excretion • Summarise phase I and II metabolism • Explain factors affecting drug elimination and
excretion • Give examples of drugs with pharmacologically
active metabolites
Pharmacokinetics and Pharmacodynamics
• Pharmacokinetics is what the body does to a drug
– i.e. the time taken for a drug to reach different areas of the body: ADME
• Pharmacodynamics is what the drug does to the body
– i.e. interaction with the receptor to cause and effect
Drug Elimination
• Elimination is the irreversible loss of drug from the body
• Requires metabolism and excretion of the drug
– Metabolism converts the drug into another molecule (metabolite) using enzymic reactions
– Excretion is the physical removal of the drug/ metabolite from the body
Metabolism
• Required to detoxify drugs and other toxic substances – E.g. plant alkaloids
• Required for elimination of a drug – Lipophilic substances not well eliminated by kidney so
need to be metabolised first – Polar substances are often excreted in urine unchanged
• Sometimes required for a drug to become active • Mostly hepatic • Occurs in two phases
– Phase I results in more chemically reactive metabolites – Phase II inactivates the metabolite via conjugation
First-Pass Metabolism
• Occurs in the liver or gut – Even if drug well absorbed from gut
• Depends upon route of administration – Much higher doses are required orally
– Differs between individuals
• Affects the amount of drug reaching the systemic circulation – Less than the dose
– So reduces bioavailability
Two Phases of Metabolism
Phase I Metabolism
• Introduction of a reactive group – E.g. OH
– Functionalisation
• Metabolite may be more toxic than the parent drug – E.g. paracetamol
• Cytochrome P450 is very important (CYP system) – Embedded in SER = microsomal
– There are some extra-hepatic P450 enzymes but don’t need to consider these here
P450 Monooxygenase System
• Superfamily of 74 haem proteins
• CYP#letter – CYP1-3 are involved in hepatic drug metabolism
• Each has a different amino acid sequence, sensitivity to inducing agents and inhibitors and specificity of substrate – Substrate specificity can overlap such that two enzymes in
the family are responsible for metabolising a drug
– You can find a list of different CYP enzymes and their drug substrates here: http://medicine.iupui.edu/clinpharm/ddis/main-table/
Phase I Reaction
• DH →DOH
• Requires P450 enzyme, O2, NADPH and NADPH-P450 reductase
P450 Monooxygenase
P450 and Biological Variation
• Species differences require that animal models are selected carefully
• Major inter-individual variation in humans – E.g. genetic polymorphisms
• Dietary and environmental factors contain inducers and inhibitors of these enzymes – Grapefruit juice inhibits and brussels sprouts induce!
– See here for a list http://medicine.iupui.edu/clinpharm/ddis/clinical-table/
– Drugs may also act on this enzyme
– E.g. ketoconazole inhibits CYP3A4
– Causes drug interactions
P450-Independent Phase I Metabolism
• Not all phase I metabolism requires CYP-mediated oxidation – E.g. alcohol uses alcohol dehydrogenase (soluble,
cytoplasmic) + CYP2E1
– Other enzymes include xanthine oxidase and monoamine oxidase
• CYP are also capable of reduction reactions e.g. warfarin metabolism by CYP2A6
• Hydrolysis may occur in plasma
Phase II Metabolism
• Conjugation of a small group to a reactive group on the drug – Sometimes provided by phase I metabolism
– E.g. hydroxyl, thiol or amino group
• Inactivates drug
• Reduces lipid solubility
• Includes the addition of glutathione, glucuronyl, sulphate, methyl, acetyl, and glycyl groups.
• Mostly occur in the liver
Drug Excretion
• Metabolites are usually cleared more quickly than the parent drug
• Main routes that drugs leave the body via: – Kidneys
• Unchanged or polar metabolites • Rates vary
– Hepatobiliary system • Increasingly important in patients with poor kidney function
– Lungs • Highly volatile substances
– Secretions • Milk or sweat
The Enterohepatic Circulation
• Glucuronide conjugates concentrated in bile
• Excreted into the gut
• Glucuronide is hydrolysed by gut enzymes
• Drug becomes active again
• Drug is reabsorbed and the cycle begins again
– Prolongs drug action
– Can account for <1/5th total drug
– E.g. morphine
Renal Excretion: Glomerular filtration
• 20kDa cut-off for filtration into the glomerulus
– Albumin is too large
• Therefore only unbound drugs able to pass through
• Only 20% blood passes into glomerulus, the rest is in the capillaries surrounding the tubules
Renal Excretion: Tubular Secretion
• Enter tubules via non-selective carriers for acidic drugs/ organic bases
• Drugs can compete for the same transporter, e.g. probenecid can prevent tubular secretion of penicillin
• Tubular secretion is the most effective means of drug elimination
• Drugs may also diffuse across the tubule – Polar drugs
– Some drugs are not metabolised and are excreted in this way, so rate of elimination determines duration of action
The Kidney
Drug Interactions
• Can occur via pharmacodynamic or pharmacokinetic mechanisms
• E.g. of pharmacodynamic drug interactions are non-competitive and physiological antagonists
• Pharmacokinetic interactions occur where one drug alters the ADME profile of another – E.g. morphine slows gastric emptying and will therefore
slow GI absorption – E.g. over 200 drugs induce enzymes and can alter
metabolism of other drugs
• Tolerance may be pharmacodynamic or pharmacokinetic – Via receptor desensitisation or enzyme induction
Manipulating Metabolism
• Some drugs must be metabolised in order to become active – These are prodrugs
– E.g. enalapril
• Some drugs have active metabolites – E.g. salycilic acid is the metabolite of aspirin. Has
anti-inflammatory but not antiplatelet activity
– E.g. Tamoxifen is metabolised into Endoxifen (100x more effective) by CYP2D6
Summary
References
Rang, H.P. Dale, M.M. Ritter, J.M. And Flower, R.J. (2007) Drug Elimination and Clearance in: Pharmacology, 6th Ed. London: Churchill Livingstone
Future Work
• Read the exam article available on Moodle
• Write a series of questions based on the article
– You can share these with your classmates
• Read articles to help you answer these questions